Journal
PLOS ONE
Volume 11, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0146102
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Funding
- BBSRC CASE award
- GSK
- Medical Research Council Program [G0600879]
- British Medical Association H. C. Roscoe Fellowships
- British Lung Foundation/Severin Wunderman Family Foundation Lung Research Program [P00/2]
- WellcomeTrust [083567/Z/07/Z]
- National Institute for Health Research (NIHR) Biomedical Research Centre
- NIHR respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation and Imperial College London
- Wellcome Trust Programme [076472/2/05/Z]
- MRC-ABPI COPDMAP consortia [G1001367/1]
- Academy of Medical Sciences
- Wellcome Trust Starter Grant award
- Asthma UK [CH11SJ] Funding Source: researchfish
- Medical Research Council [G0600879] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10148, CL-2008-21-014] Funding Source: researchfish
- MRC [G0600879] Funding Source: UKRI
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Introduction Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from nonsmokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1 alpha binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1a in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1 alpha levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
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